APPLICANT'S ABSTRACT: During the late 1980's, the previous decline in tuberculosis ceased and rates began to rise, heralding a resurgence of disease. Human immunodeficiency virus infection is largely responsible for the excess number of cases. A co-factor for TB infection is alcohol consumption. Alcohol is immunosuppressive, and facilitates acquisition of pulmonary infections through malnutrition, greater propensity for indulging in high risk behaviors, and alteration of normal host defenses. Defense alterations include changes in immune effector cell populations and down regulation of cytokine production and/or function, which are critical components in the containment of intracellular pathogens, such as Mycobacterium tuberculosis. We hypothesize that alcohol adversely alters pulmonary host defense mechanisms against Mycobacterium tuberculosis by disrupting early cytokine interactions [tumor necrosis factor (TNF), interleukin (IL)-12, and interferon (IFN)-gamma] which are critical in the orchestration of effective Th1 CD4+ lymphocyte cell-mediated responses to contain the mycobacteria. We will test this hypothesis in a murine model of acute and chronic alcohol consumption and M. tuberculosis infection, initially employing mycobacterial lipoarabinomannan (LAM; a cell wall component) and nonviable organisms as probes, and subsequently utilizing an in vivo model of M. tuberculosis infection. To achieve this, we propose the following: Specific Aim 1: To test the prediction that alcohol consumption suppresses the pulmonary production of early cytokines in response to mycobacterial antigens in mice. Specific Aim 2: To test the theory that alcohol, through disruption of early cytokine pathways, impairs the development of Th1-directed cell-mediated immunity to viable M. tuberculosis infection. Specific Aim 3: To demonstrate that defective antimycobacterial cell-mediated host defenses can be enhanced with IFN-gamma organ specific cytokine gene therapy in an animal model. Our goal is to elucidate the mechanisms by which alcohol consumption further diminishes host resistance to M. tuberculosis infection.